Identification of dual inhibitors against BACE1 and GSK-3β for the treatment of Alzheimer’s disease: An in silico-based approach

Abstract

Abstract Alzheimer’s disease (AD) has no Food and Drug Administration (FDA) approved drugs that can halt neurodegeneration. To halt neurodegeneration, targeting the major pathways underlying in AD might be the potential strategy. One such pathways are Amyloid-β (Aβ) and tau pathways which are majorly regulated by β- amyloid precursor protein cleaving enzyme 1 (BACE1) and Glycogen synthase kinase (GSK-3β) respectively. BACE1 is a crucial enzyme involved in Aβ formation & generation and GSK-3β is one of the major kinases responsible for hyperphosphorylation of tau protein. The present study aimed to identify BACE1 and GSK-3β dual inhibitors by an in silico-based approach. Structure based virtual screening has been carried out by using 7,498 Zinc database molecules against BACE1 (PDB ID: 3TPP), and GSK-3β (PDB ID: 1Q3W). 3 hits against BACE1 have identified in Virtual screening with docking score ranging from -8.03 to -12.07 & glide energy ranging from -50.92 to -53.88 kcal/mol and 3 hits against GSK-3β with a docking score ranging from -10.59 to -10.85 & glide energy ranging from -40.5 to -49.7 kcal/mol. Based on amino acid interactions, docking score, and MMGBSA binding energy with BACE1 and GSK-3β active sites, hit molecule ZINC000034853956 with a docking score of -8.03 & -10.59 and glide energy of -53.27 & -49.7 Kcal/mol was selected. MMGBSA binding energy of ZINC000034853956 to BACE1 is -88.41 kcal/mol and to GSK-3β is -15.46 kcal/mol and found to have better affinity than other hit molecules. Further, Molecular dynamics (MD) simulation was performed for the same molecule and MD analysis revealed significant interaction with both the proteins. The present study successfully identified a hit molecule as a BACE1 and GSK-3β dual inhibitor for the treatment of AD.